The cellular context of T cell signaling

Abstract

Classical alphabeta T cells protect the host by monitoring intracellular and extracellular proteins in a two-step process. The first step is protein degradation and combination with a major histocompatibility complex (MHC) molecule, leading to surface expression of this amalgam (antigen processing). The second step is the interaction of the T cell receptor with the MHC-peptide complex, leading to signaling in the T cells (antigen recognition). The context for this interaction is a T cell-antigen presenting cell junction, known as an immunological synapse if symmetric and stable and as a kinapse if asymmetric and mobile. The physiological recognition of a ligand takes place most efficiently in the F-actin-rich lamellipodium and is F-actin dependent in stages of formation and triggering and myosin II dependent for signal amplification. This review discusses how these concepts emerged from early studies on adhesion, signaling, and cell biology of T cells.

Figure 1

Synapses vs Kinases. Schematic of multilayer actin cytoskeleton in the periphery of the immunological synapse. Based on (Giannone et al., 2007). Centripetal action flow is involved in antigen gathering. When this system is symmetric the cell forms a stable synapse. When it’s asymmetric the cell gains net traction and crawls using the same machinery. The cSMAC of a synapse forming cells is similar to the uropod of a migrating cell in that the amounts of F-actin are relatively low and integrins are disengaged, but otherwise these structures are very different and this is one of the most striking differences between the synapse and kinapse modes of signal integration.

Figure 2

Model for TCR triggering involving translocation between membrane domains with different levels of acidic lipids. The bulk plasma membrane is red (negatively charged) and this would maintain ITAMs buried in membrane (grey). The overlaying actin network of the T cells is represented by an electron micrograph of lamellipodial actin (Svitkina et al., 1997). In the absence of specific TCR ligands, the TCR (grey stars) are loosely corralled by actin network, but diffuse independently within corrals and cannot be forced to enter more neutral rafts because this is unfavorable and the actin can’t exert enough force on one TCR to prevent the TCR from jumping out through hop diffusion (Kusumi et al., 2005). Monovalent MHC-peptide agonists induce direct clustering of TCR and stronger linkage to actin, which then produces enough force to move the TCR microcluster into a neutral domain where CD45 is excluded and active Src can diffuse in to phosphorylated the dissociated ITAM (green stars). This more neutral lipid domain, which itself can be anchored to the cortical cytoskeleton can be intermittently dragged with the TCR microcluster to sustain signaling until the system reaches the cSMAC.